Project Summary Although chronic obstructive pulmonary disease (COPD) occurs predominantly in smokers, it is unknown why only a minority of smokers (~20-40%) develops chronic airflow limitation and/or destruction of distal airspaces (emphysema). Using several NIH and foundation grants, we have systematically generated genetic, genomics, proteomic, and metabolomics profiles from the NHLBI supported COPDGene cohort, which includes 10,300 current and former smokers age 45-80. This proposal will focus on integrating the omics data generated in the five-year followup (Phase II) of the COPDgene study to identify molecular subtypes of COPD across a broad range of blood profiles (Specific Aim 1). Biomarkers and pathways discriminating the molecular subtypes, in addition to other COPD phenotypes will then be identified (Specific Aim 2). These results will identify markers that are specific to smoking-related lung disease and can be used to develop novel diagnostic tests and therapies for early prevention and treatment of COPD.